Extrarenal Production of 1,25-Dihydroxyvitamin D and Clinical Implications

Abstract

This chapter addresses the pathophysiology and cellular biochemistry of dysregulated vitamin D metabolism that occurs in some patients with granuloma-forming and malignant lymphoproliferative disorders. The principal focus of discussion is the human granuloma-forming disease sarcoidosis. Of all of the human conditions associated with the extrarenal overproduction of an active vitamin D metabolite with consequent endogenous vitamin D intoxication, sarcoidosis is the most commonly recognized and most carefully studied. Hence the first part of the chapter reviews what is known about the mechanics and regulation of the vitamin D-metabolizing enzymes present in human inflammatory cells. This is followed by a discussion of the diagnosis, treatment, and prevention of hypercalcemia and hypercalciuria in patients suffering from endogenous vitamin D intoxication. The concluding portion of the chapter addresses the issue of why active vitamin D metabolites are made in these diseases. There is now consensus agreement among investigators in the vitamin D and immunology fields that macrophage-derived vitamin D metabolites can play an important role in the modulation of the local human immune response in these diseases. The reader is referred to other chapters in the text that discuss in detail some of the noncalcemic (Chapter 13) and nongenomic (Chapter 12) actions of vitamin D metabolites and analogs (Chapter 25) that are particularly relevant to the issue of the immunomodulatory effects of vitamin Ds in human disease (i.e., cancer and psoriasis).